Abstract：
Benzophenone-3 (BP-3) and its major metabolite benzophenone-1 (BP-1) are widely used as UV filters in sunscreens and cosmetics to prevent sunburn and skin damage, or as stabilizers to prevent photodegradation in many commercial products. As a result, their presence is ubiquitous in the environment, wildlife and humans. Based on endocrine disruption concerns, international regulatory agencies are performing a closer evaluation.
This work aimed to comprehensively review the available human relevant evidence for safety issues in MEDLINE/PubMed in order to create a structured database of studies, as well as to conduct an integrative analysis as part of the Human Biomonitoring for Europe (HBM4EU) Initiative.
A total of 1,635 titles and abstracts were screened and 254 references were evaluated and tabulated in detail, and classified in different categories: i) exposure sources and predictors; ii) human biomonitoring (HBM) exposure levels to perform a meta-analysis; iii) toxicokinetic data in both experimental animals and humans; iv) in vitro and in vivo rodent toxicity studies; and v) human data on effect biomarkers and health outcomes. Our integrative analysis showed that internal peak BP-3 concentrations achieved after a single whole-body application of a commercially available sunscreen (4% w/w) may overlap with concentrations eliciting endocrine disrupting effects in vitro, and with internal concentrations causing in vivo adverse female reproductive effects in rodents that were supported by still limited human data. The adverse effects in rodents included prolonged estrous cycle, altered uterine estrogen receptor gene expression, endometrium hyperplasia and altered proliferation and histology of the mammary gland, while human data indicated menstrual cycle hormonal alterations and increased risk of uterine fibroids and endometriosis. Among the modes of action reported (estrogenic, anti-androgenic, thyroid, etc.), BP-3 and especially BP-1 showed estrogenic activity at human-relevant concentrations, in agreement with the observed alterations in female reproductive endpoints. The meta-analysis of HBM studies identified a higher concern for North Americans, showing urinary BP-3 concentrations on average 10 and 20 times higher than European and Asian populations, respectively.
Our work supports that these benzophenones present endocrine disrupting properties, endorsing recent European regulatory efforts to limit human exposure. The reproducible and comprehensive database generated may constitute a point of departure in future risk assessments to support regulatory initiatives. Meanwhile, individuals should not refrain from sunscreen use. Commercially available formulations using inorganic UV filters that are practically not absorbed into systemic circulation may be recommended to susceptible populations.
This work aimed to comprehensively review the available human relevant evidence for safety issues in MEDLINE/PubMed in order to create a structured database of studies, as well as to conduct an integrative analysis as part of the Human Biomonitoring for Europe (HBM4EU) Initiative.
A total of 1,635 titles and abstracts were screened and 254 references were evaluated and tabulated in detail, and classified in different categories: i) exposure sources and predictors; ii) human biomonitoring (HBM) exposure levels to perform a meta-analysis; iii) toxicokinetic data in both experimental animals and humans; iv) in vitro and in vivo rodent toxicity studies; and v) human data on effect biomarkers and health outcomes. Our integrative analysis showed that internal peak BP-3 concentrations achieved after a single whole-body application of a commercially available sunscreen (4% w/w) may overlap with concentrations eliciting endocrine disrupting effects in vitro, and with internal concentrations causing in vivo adverse female reproductive effects in rodents that were supported by still limited human data. The adverse effects in rodents included prolonged estrous cycle, altered uterine estrogen receptor gene expression, endometrium hyperplasia and altered proliferation and histology of the mammary gland, while human data indicated menstrual cycle hormonal alterations and increased risk of uterine fibroids and endometriosis. Among the modes of action reported (estrogenic, anti-androgenic, thyroid, etc.), BP-3 and especially BP-1 showed estrogenic activity at human-relevant concentrations, in agreement with the observed alterations in female reproductive endpoints. The meta-analysis of HBM studies identified a higher concern for North Americans, showing urinary BP-3 concentrations on average 10 and 20 times higher than European and Asian populations, respectively.
Our work supports that these benzophenones present endocrine disrupting properties, endorsing recent European regulatory efforts to limit human exposure. The reproducible and comprehensive database generated may constitute a point of departure in future risk assessments to support regulatory initiatives. Meanwhile, individuals should not refrain from sunscreen use. Commercially available formulations using inorganic UV filters that are practically not absorbed into systemic circulation may be recommended to susceptible populations.
摘要：
背景：二苯甲酮-3（BP-3）及其主要代谢产物二苯甲酮-1（BP-1）被广泛用作防晒霜和化妆品中的紫外线过滤剂，以防止晒伤和皮肤损伤，或作为稳定剂以防止许多商业产品中的光降解。因此,它们在环境中无处不在，野生动物和人类。基于对内分泌干扰的担忧，国际监管机构正在进行更密切的评估。
目的：这项工作旨在全面审查MEDLINE/PubMed中有关安全问题的人类相关证据，以创建结构化的研究数据库，以及作为欧洲人类生物监测（HBM4EU）计划的一部分进行综合分析。
结果：总共筛选了1,635个标题和摘要，并对254个参考文献进行了详细评估和列表，并分为不同类别：i）暴露源和预测因子；ii）人类生物监测（HBM）暴露水平以进行荟萃分析；iii）实验动物和人类的毒物动力学数据；iv）体外和体内啮齿动物毒性研究；v）关于生物标志物和健康结果的人类数据。我们的综合分析表明，单次全身应用市售防晒霜（4％w/w）后达到的内部峰值BP-3浓度可能与体外引起内分泌干扰作用的浓度重叠，并且内部浓度在啮齿动物中引起体内对雌性生殖的不利影响，而人类数据仍然有限。啮齿动物的不良反应包括延长发情周期，改变子宫雌激素受体基因表达，子宫内膜增生和乳腺增生和组织学改变，而人类数据表明月经周期激素改变和子宫肌瘤和子宫内膜异位症的风险增加。在报告的作用方式中(雌激素，抗雄激素,甲状腺，等。),BP-3，尤其是BP-1在人类相关浓度下显示出雌激素活性，与观察到的女性生殖终点变化一致。对HBM研究的荟萃分析发现，北美人受到了更高的关注，显示尿BP-3浓度平均比欧洲和亚洲人群高10和20倍，分别。
结论：我们的工作支持这些二苯甲酮具有内分泌干扰特性，支持欧洲最近限制人类接触的监管努力。生成的可重复和全面的数据库可能构成未来风险评估的出发点，以支持监管举措。同时,个人不应避免使用防晒霜。使用实际上不被吸收到体循环中的无机UV过滤剂的市售制剂可以推荐给易感人群。
目的：这项工作旨在全面审查MEDLINE/PubMed中有关安全问题的人类相关证据，以创建结构化的研究数据库，
结果：总共筛选了1,635个标题和摘要，并对254个参考文献进行了详细评估和列表，
结论：我们的工作支持这些二苯甲酮具有内分泌干扰特性，
